Patent DE-10309927-A1 (DE)
Title: New trisubstituted dihydro-imidazo-pyridazinone or imidazo-pyridinone derivatives, useful as dipeptidylpeptidase-IV inhibitors for e.g. treating diabetes mellitus type I or II, arthritis or obesity
Inventor: HAUEL NORBERT
IPC: C07D487/04
Filed: 2003-03-07
Abstract: 2,3,5-Trisubstituted 3,5-dihydro-imidazol-(4,5-d)-pyridazin-4-one or 3,5-dihydro-imidazo-(4,5-c)-pyridin-4-one derivatives (I) and their tautomers, enantiomers, diastereomers (or mixtures) and salts are new. 2,3,5-Trisubstituted 3,5-dihydro-imidazol-(4,5-d)-pyridazin-4-one or 3,5-dihydro-imidazo-(4,5-c)-pyridin-4-one derivatives of formula (I) and their tautomers, enantiomers, diastereomers (or mixtures) and salts are new: [Image] X : N or CR 5>; R 5>H or Me; R 1>5-7 membered cycloalkyleneimino (C-substituted by amino and optionally substituted (os) by alkyl), 6- or 7-membered cycloalkyleneimino (with CH 2 in the 4-position replaced by NH), or 5-7C cycloalkylamino (where the cycloalkyl is substituted by amino or the CH 2 in the 3-position is replaced by NH); R 2>benzyl (os in the ring by 1 or 2 F, Cl or Br or by CN), 3-8C alkenyl, 3-5C alkynyl, (3-7C) cycloalkylmethyl, (5-7C) cycloalkenylmethyl, furylmethyl, thienylmethyl, pyrrolylmethyl, thiazolylmethyl, imidazolylmethyl, pyridinylmethyl, pyrimidinylmethyl, pyridazinylmethyl or pyrazinylmethyl; R 3>1-6C alkyl, phenylalkyl or naphthylalkyl (both os in the ring by halo, CN, alkyl or OMe), 2-phenyl-2-hydroxyethyl, phenylcarbonylmethyl (os in the ring by OH, alkoxy, aminocarbonyl-alkoxy, N-alkyl- or N,N-dialkylaminocarbonyl-alkoxy, NH 2, alkylcarbonylamino, 3-6C cycloalkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino or CONH 2), (3-methyl-2-oxo-2,3-dihydro-benzoxazolyl)-carbonylmethyl, thienylcarbonylmethyl, Het-alkyl, imidazo-(1,2-a)-pyridin-2-yl-methyl, 5-methylimidazo-(1,2-a)-pyridin-2-yl-methyl, 1,5-naphthyridin-2-ylmethyl, 1,2,4-triazolo-(4,3-a)-pyridin-3-ylmethyl, (Z)-3-(pentafluorophenyl)-prop-2-enyl, 1-(R 6>)-2-oxo-1,2-dihydroquinolin-4-ylmethyl, 1-(R 6>)-2-oxo-1,2-dihydroquinolin-6-ylmethyl or 2-(R 6>)-1-oxo-1,2-dihydroisoquinolin-4-ylmethyl; Het : 5- or 6-membered monocyclic heteroaryl (os by 1 or 2 alkyl or by morpholino, pyridyl or phenyl), where 6-membered heteroaryl contains 1-3 N, 5-membered heteroaryl contains one N, N(alkyl), N(phenylalkyl), O or S (optionally together with 1-3 further N) and the heteroaryl rings are optionally fused with a benzo ring (os by one halo, 1 or 2 alkyl, one CF 3 or one OMe), the benzoheterocyclic groups being bonded via the heterocycle or the benzo ring; R 6>H or Me; and R 4>H or alkyl. Alkyl moieties have 1-3C unless specified otherwise, and (m)ethyl are os by F. An independent claim is also included for the preparation of (I). ACTIVITY : Antidiabetic; Antiarthritic; Anorectic; Immunosuppressive; Osteopathic; Antilipemic; Antiarteriosclerotic; Tranquilizer; Cardiant; Diuretic; Hypotensive; Nephrotropic; Antiinflammatory; Antiinfertility. MECHANISM OF ACTION : Dipeptidylpeptidase-IV (DPP-IV) inhibitor; B-cell degeneration inhibitor; Glucagon-like peptide (GLP) action modulator. 2-(3-Amino-piperidin-1-yl)-3-(but-2-ynyl)-5-(quinoxalin-6-ylmethyl)-3,5-dihydro-imidazol-(4,5-d)-pyridazin-4-one (Ia) had IC 5 0 1.2 nM for inhibition of DPP-IV.